Studies on the CALL gene (3p26.3): The gene CALL (cell adhesion L1 like) encodes a trans-membrane cell adhesion molecule (CAM) capable of both homotypic and heterotypic binding. We showed CALL is expressed in normal tissues beside the brain and is over-expressed in a variety of human tumors. Our expression studies suggest that CALL may contribute to cancer invasive growth and metastasis, depending on stage and tissue it may act either as a tumor suppressor or oncogene. This validates CALL as a biomarker of invasive tumor growth and metastasis and a novel target for personalized immune intervention. Studies on the VHL gene (3p25.3): We identified the VHL epigenetic code and recreated its patterns in transgenic mice; we found that CTCF a ubiquitous chromatin insulator/DNA binding protein has a binding site in VHL CpG promoter island and may play along with other transcription factors an important role in protecting against aberrant silencing of the gene. In cancer we propose VHL is universally mutated/silenced to promote tumor progression, spread and facilitate the creation of cancer stem cells. We discovered that VHL targets, CA 9 /CA12 genes, are specifically induced and over-expressed in many tumor types. They may control the acidic tumor microenvironment and should be considered molecular targets for development of new treatment modalities. We identified several compounds that showed nanomolar inhibition specific for each CAIX and CAXII enzyme. We discovered that STRA13 modulates the activity of STAT1 and STAT3. We outlined a set of targets common for pVHL and TGF-beta1 pathways. These results emphasize a new mechanism that employs relay genes to amplify and diversify the original primary hypoxia signal. We suggest VHL may be involved in the creation of cancer stem cells (CSC) harboring cancer-causing mutations. Studies on 3p21.3 cancer-causing genes: The PL6 protein binds to and modulates the function of two similar progesterone receptors (MAPRs) localized in the endoplasmic reticulum. We showed that PL6 is a hypoxia independent target of VHL; its expression is absent in VHL disease tumors and sporadic CCRCC. PL6 is a biomarker of CCRCC and controls Acy1. We validated the tumor suppressor function of the NPRL2 gene; bioinformatics analysis suggests it may be a potential novel mismatch repair gene and a target of cisplatin. We identified the RASSF1A gene as a multiple TSG involved in many tumors, including lung, breast, prostate, kidney, head & neck, uterine cervix and others. We discovered that RASSF1A is a target of somatic hyper mutability in several human cancers. We created Fus1 null mutants that showed consistent changes in NK cells and serum antibody profiles coupled with changes in the expression of important genes regulating the innate immune system suggesting involvement of Fus1 in the development and activation of the mammalian innate immune system. FUS1 may be used to boost innate immunity in cancer and other immunodeficient diseases. The HYAL2 protein was identified as a GPI-anchored receptor for the sheep lung cancer retrovirus, JSRV, and a sequestration mechanism inactivating HYAL2 protein was demonstrated. This leads to ligand-independent activation of the RON receptor tyrosine kinase and its downstream signaling pathways (Akt and MAPK). We also identified the essential amino acid residues in the sheep/human Hyal2 receptor that determine specific efficient binding and entry of the JSRV. We discovered that in SCLC the promoter of RON is silenced by hypermethylation leading to simultaneous activation of a putative internal promoter. The novel transcript originating from this internal promoter encodes mostly the cytoplasmic portion of the receptor that is constitutively activated and drives cell proliferation Studies on the 3p12.3 gene: Our hunt for the TSG in 3p12.3 resulted in the discovery of two novel ncRNA genes that may function as TSG in lung and breast cancers. These ncRNA genes may harbor HAR elements (human accelerated regions) uniquely involved in the evolution of the human brain. . Current plans are focused: On experimental validation of combined gene therapy of cancer with cancer-causing TSG directed at cancer stem cells (CSC) and patients HSC using cell surface pH regulators as immune, drug, and delivery targets to cure cancer. Contributions (patents, public databases, reagents): In July 2006 NCI filled for a patent entitled: Methods and Compositions for Treating Fus1 Related Disorders Publication number: WO/2007/008671. International Publication Date January 18, 2007. Numerous reagents resulting from our research were freely and promptly distributed to a large number of US and EU research laboratories